Inflammation of the soft tissues (gingivae) around teeth is referred to as gingivitis, and may be caused by microbial infection. In the case of progressive infection, direct microbial actions as well as the production of tissue-destructive enzymes such as collagenase, with or without stimulation of host tissue-destructive enzyme activity by the infectious agents, can lead to destruction of supporting tissues around the teeth, a condition referred to as periodontitis (Klausen et al., 1991). The subgingival microbiota associated with these peridental conditions may be comprised of multiple species, and may change during the course and progression of these dental infections. Gram-negative anaerobic bacteria, in particular, are known to play an essential role.
Refractory periodontitis and gingivitis patients, who often suffer from specific infections, are prime candidates for antimicrobial therapy. Unfortunately, the results of most published clinical studies on antibiotic periodontal therapy are ambiguous, primarily because of issues related to susceptibility of causative pathogens to the treatment choice (Slots and Rams, 1990). In addition, few antimicrobial agents have been identified which are active against anaerobic bacteria, and still fewer have activity against gram-negative anaerobic bacteria (e.g., U.S. Pat. No. 4,997,830; Baker et al., 1983). Further, species involved in peridental infections, such as Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis (formerly Bacterioides gingivalis), are refractory to conventional therapies, including chemotherapies (e.g., Tanner and Stillman, 1993; U.S. Pat. No. 4,997,830).
Some of the pathogens involved in peridental infections, such as P. gingivalis, both produce tissue-destructive enzymes such as collagenase and induce the production of collagenolytic enzymes by the host tissues (Evans et al., 1991). By attacking the structural protein collagen, this activity mitigates the structural integrity of the peridental tissues, promoting the destruction of these tissues and loss of alveolar support. This activity therefore directly contributes to the development and progression of periodontal disease, leading to bone loss and possibly tooth loss.
There is a strong association between the eradication of ineffective microorganisms and the success of treatment of dental infections such as gingivitis and periodontal disease. Current therapies for peridental infection include the debridement of infected sites and surgical intervention accompanied by antimicrobial therapy.
Penicillins in general are highly effective antimicrobial compositions against anaerobic bacteria. Some penicillins, such as Amoxicillin, have antimicrobial activity against anaerobic bacteria and some gram-negative bacterial species. Nevertheless, both Penicillin G and Amoxicillin have been shown to be ineffective against bacterial species important in peridental infections, such as P. gingivalis.
Tetracyclines are impressively broad spectrum antimicrobial agents, with activity against a wide range of bacterial and non-bacterial species. However, tetracyclines have a number of disadvantages relative to use in dental medicine which are related to their bacteriostatic mechanism of action and broad spectrum activity. For example, the rapid emergence of bacterial strains which are resistant to tetracyclines and the occurrence of overgrowth of unsusceptible pathogens, such as Candida, during treatment constitute serious limitations to the use of this class of antimicrobials in the treatment or prevention of dental infections leading to tooth loss.
Short term treatment of peridental infection with tetracyclines is often ineffective, or can result in the suppression of the peridental infection during treatment and the subsequent recurrence of infection following cessation of treatment. Longer term treatment (e.g., 3 weeks) has even been shown to increase the growth of potential pathogens via the development of bacterial resistance to tetracyclines and the overgrowth of unsusceptible pathogens. (Slots and Rams, 1990). The broad spectrum of activity of tetracyclines can result in superinfection of the diseased tissue by bacteria which are unsusceptible to its antimicrobial action, and can also result in opportunistic infection of healthy tissues. Prolonged or frequent treatment courses with broad spectrum antimicrobials enable superinfecting organisms to persist in the subgingival microbial community over extended periods of time, contributing to therapeutic failure (i.e., refractory infection). Opportunistic pathogens may also give rise to systemic complications (Slots and Rams, 1990).
The spectrum of antimicrobial effectiveness of currently used therapeutic compounds is summarized below.
__________________________________________________________________________ Antimicrobial Activity Against Activity Against Activity Against Activity against Agent Anaerobes Gr- Gr- Anaerobes A. act and/or P. gin __________________________________________________________________________ Clindamycin + - - N/A.sup.1 Metronidazole + .+-. .+-. ineffective.sup.2 2.sup.d -generation + .+-. N/A none described Cephalosporins Penicillin G + - N/A ineffective.sup.3 Amoxicillin + + .+-. ineffective.sup.2 Tetracyclines + + + partially effective.sup.4 __________________________________________________________________________ .sup.1 N/A = not applicable, by limitations in the spectrum of activity. .sup.2 US 4,997,830 .sup.3 Wadsworth et al., p. 114-5. .sup.4 The current standard of care, used as reference standard in the instant application.
Additional limitations in dental practice include the tendency of tetracyclines to bind calcium, which can lead to bone and tooth discoloration and dysgenesis. These agents are thereby contraindicated for use in children and pregnant women. Thus, tetracyclines are unsuitable for the treatment of juvenile periodontitis or the forms of gingivitis associated with pregnancy.
The limitations and disadvantages described above for the currently used antimicrobial agents expose the continued need for effective treatment of these dental infections and the discovery and development of antimicrobial agents with activity against the etiological microbes specifically. In order to obviate some of the problems associated with currently employed antimicrobial therapies, such agents ideally should exhibit relatively narrow spectra of activity, while being effective agents against some or all of the relevant oral pathogens.
It is one object of this invention to provide antimicrobially effective compositions having narrow spectra of activity for the treatment of peridental infection. It is another object of this invention to provide a method for treating peridental infections with antimicrobially effective compositions which are active against a narrow spectrum of bacteria. It is a further objective of this invention to provide a method for treating gram-negative anaerobic bacterial infections with compositions that are effective against a narrow spectrum of bacteria. Such antimicrobial agents would also be useful for many other purposes, for example, as an antibacterial agent for in vitro cell culture, a pharmaceutical preservative, an industrial preservative (for example in dyes), and an industrial antibacterial additive to cleaning solutions.